This is a K08 award application for Dr. Salvatore Spina, a behavioral neurology fellow and clinical instructor at the University of California, San Francisco, Memory and Aging Center who is establishing himself as an independent investigator as a clinician-scientist focusing on neuropathological substrates of brain network dysfunction. This K08 award will provide Dr. Spina with the necessary support to accomplish the following: (1) gain expertise in molecular and cellular mechanisms leading to neurodegeneration; (2) develop proficiency in the use of structural and functional MRI methodologies; (3) gain expertise in the use of cutting-edge methodologies for quantification of molecular markers of degeneration by the use of an innovative multiplexed fluorescence platform; (4) gain experience on the significance of proteomics and mass-spectrometry data of protein post-translational modifications as they relate to neurodegeneration; (5) advance his knowledge of biostatistics; and (6) develop an independent research career. To achieve these goals, Dr. Spina has assembled a multidisciplinary mentoring team with primary mentor Dr. William Seeley (a behavioral neurologist with expertise in neuropathology and functional imaging); two co-mentors: Dr. Bruce Miller (a neurologist with expertise in behavior, neurodegenerative disease, and clinical research) and Dr. Lennart Mucke (a neurologist and neuroscientist with expertise in molecular biology and experimental models of neurodegeneration); and five advisors: Dr. Lea Grinberg (a neuropathologist with expertise on selective neuronal vulnerability and stereological neuropathological methodologies); Dr. Eric Huang (a neuropathologist with expertise in neurodevelopment and neurodegeneration); Dr. John Kornak (a biostatistician with expertise on statistical analysis of neurodegenerative diseases); Dr. Julie Schneider (a neuropathologist with expertise on brain aging and TDP-43 proteinopathies); and Dr. Judith Steen (a neurologist with expertise in proteomics, mass- spectrometry and tau-protein post-translational modifications). The proposed research investigates the relationship between in-vivo neuroimaging markers of neurodegeneration and neuronal dysfunction, and post-mortem molecular markers of disease pathogenesis. The central hypothesis is that brain network vulnerability, imaging changes, and disease phenotypic expression are driven by selective and distinct molecular pathways of neurodegeneration in tauopathies and TDP-43 proteinopathies. We will collect imaging data on a well-characterized cohort of subjects with diverse types of frontotemporal lobar degeneration syndromes and will analyze the correlations with neuropathological findings assessed in post-mortem neuropathological specimens from the same individuals. We will establish correlations between regional brain atrophy or reduced brain network integrity, and both semi-quantitative and quantitative measures of neurodegeneration (Aim 1). We will assess correlations between regional brain volume loss or impaired intrinsic connectivity and quantitative measures of a large scale of molecular markers as assessed by multiplexed fluorescence (Aim 2). We will explore correlations between specific profiles of tau protein post-translational modifications in tauopathies with imaging measures of regional neurodegeneration and network dysfunction, as well as with quantitative measures of molecular markers of disease pathogenesis (Aim 3). This research will increase the understanding of the neuropathological substrate of neurodegeneration and brain network dysfunction, direct future studies for the identification of new potential targets of disease treatment, and provide insights on the use of neuroimaging methodologies for the prediction of specific molecular mechanisms of degeneration in-vivo. This K08 training will enable Dr. Spina to apply concepts of selective vulnerability to the understanding of neurodegenerative diseases.